EP0583606A2 - Nouveaux hydrazono-5-béta, 14-béta-androstanes cardioactifs, procédé pour leur préparation et les compositions pharmaceutiques les renfermant - Google Patents
Nouveaux hydrazono-5-béta, 14-béta-androstanes cardioactifs, procédé pour leur préparation et les compositions pharmaceutiques les renfermant Download PDFInfo
- Publication number
- EP0583606A2 EP0583606A2 EP93111120A EP93111120A EP0583606A2 EP 0583606 A2 EP0583606 A2 EP 0583606A2 EP 93111120 A EP93111120 A EP 93111120A EP 93111120 A EP93111120 A EP 93111120A EP 0583606 A2 EP0583606 A2 EP 0583606A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- androstane
- aminopropoxy
- diol
- imidazolin
- hydrazonomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Definitions
- the present invention relates to new 17-hydrazonomethyl- and 17-hydrazono-14 ⁇ -hydroxy-5 ⁇ -an- drostane derivatives active on the cardiovascular system, to a process for their preparation and to pharmaceutical compositions containing same for the treatment of cardiovascular disorders, such as heart failure and hypertension.
- pharmaceutical acceptable salts are included in the scope of the invention.
- Pharmaceutical acceptable salts are salts which retain the biological activity of the base and are derived from such known pharmacologically acceptable acids such as, e. g., hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, oxalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid and others commonly used in the art.
- the compounds of the invention also include solvates (e.g. hydrates).
- N-oxides where the nitrogen atom is not substituted with a hydrogen atom, are also encompassed by the invention.
- the alkyl groups are branched or straight chain groups or cyclic groups.
- the C2-C4 alkyl is preferably ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl.
- the C1-C4 alkyl is preferably methyl, ethyl, n-Propyl, iso-propyl, n-butyl, tert-butyl.
- the C2-C4 acyl is preferably acetyl, propionyl, n-butyryl or iso-butyryl.
- the R 4 group is preferably hydrogen, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 2-(1-pyrrolidinyl)ethyl, 3-(1-pyrrolidinyl)-propyl.
- the R 5 group is preferably hydrogen, methyl, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(1-pyrrolidinyl)ethyl, 3-(1-pyrrolidinyl)propyl, acetyl, phenyl.
- the NR 6 R 7 group is preferably amino, methylamino, dimethylamino, diethylamino, iso-propylamino, pyrrolidinyl, piperidyl, morfolino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl, 4-(2-dimethylaminoethyl)piperazin-1-yl, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, (2-dimethylaminoethyl)-methylamino, (2-diethylaminoethyl)methylamino, 3-dimethylaminopropylamino, (3-dimethylaminopropyl)methylamino, 2-(1-pyrrolidinyl)-ethylamino, 3-(1-pyrrolidinyl)propylamino, (2-(1-pyrrol
- the NR9R'O group is preferably amino, methylamino, dimethylamino, ethylamino, diethylamino, iso-propylamino, pyrrolidinyl, morfolino.
- R 5 and R 6 groups taken together with the heteroatom they are linked to are preferably 2-imidazolin-2-yl, 1-methyl-2-imidazolin-2-yl, 5-oxo-2-imidazolin-2-yl, 1-methyl-5-oxo-2-imidazolin-2-yl, 2-imidazolyl, 2-(1-methyl)imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, 1-methyl-1,4,5,6-tetrahydro-2-pyrimidinyl, 1,4,5,6-tetrahydro-6-oxo-2-pyrimidinyl or 1-methyl-1,4,5,6-tetrahydro-6-oxo-2-pyrimidinyl.
- 3,8-(3-aminopropoxy) substituents also the corresponding 3 ⁇ -(3-dimethylaminopropoxy), 3,8-(3-diethylaminopropoxy), 3 ⁇ -(3-(1-pyrrolidinyl)propoxy), 3,8-(2-aminoethoxy), 3 ⁇ -(2-dimethylaminoethoxy), 3,8-(2-diethylaminoethoxy) and 3 ⁇ -(2-(1-pyrrolidinyl)ethoxy) compounds.
- 17-Guanidinoiminomethyl-5 ⁇ -androstane-3 ⁇ ,14 ⁇ -diol and 17-guanidinoimino-5 ⁇ -androstane-3 ⁇ ,14 ⁇ -diol are reported to be weak inhibitors of Na + ,K +- ATPase and weak positive inotropic agents (Gelbart A. and Thomas R., J. Med. Chem., 1978, 21, 284; Schönfeld W. and Repke K., Quant. Struct.-Act. Relat., 1988, 7, 160).
- the invention furthermore provides a process for the preparation of compounds of general formula I, which comprises a condensation reaction of compounds of formula II in which: Y and the symbol --- are as above defined and D has the following meanings: where R 2 and R 3 are as above defined, with a compound of general formula III and IV to give compounds of general formula I where R 1 is as above defined.
- Compounds (III) and (IV) can be used as the free base or in the form of a salt with an acid such as. e.g., hydrochloric, carbonic, oxalic, hydriodic or sulfuric acid.
- the reaction can be carried out in a solvent, such as ethanol, methanol, acetonitrile, dioxane, tetrahydrofuran, water or a mixture of said solvents, at a temperature between 0 °C and the boiling point of the above mentioned solvents or of their mixtures.
- a solvent such as ethanol, methanol, acetonitrile, dioxane, tetrahydrofuran, water or a mixture of said solvents.
- additional salts such as, e.g., NaH 2 P0 4 , Na 2 HP0 4 , NaOAc
- acids such as, e.g., hydrochloric, sulfuric, acetic, phosphoric acid
- bases such as, e.g., sodium or potassium hydroxide
- the unknown 3 ⁇ -hydroxy compounds are prepared from the corresponding known 3-keto compounds by reduction with Li-selectride.
- the 17a-hydroxy-20-carbonyl compounds are unknown compounds they are obtained from the corresponding 17a-hydrogen-20-carbonyl compounds by careful oxidation with selenium dioxide e.g. in dioxane in the presence of a base, such as pyridine or triethylamine, at a temperature ranging from 20 ° C to the boiling point of the solvent.
- a base such as pyridine or triethylamine
- Unknown 17a-pregnanes and 17a-formylandrostanes derivatives are prepared from the corresponding 20-oxo-17- epimeric compounds unsubstituted in position 17a by isomerization in alkaline conditions.
- the introduction of the hydroxy group in position 17 ⁇ is performed with the methods described above for the corresponding 17 epimers.
- the groups optionally present in Y and/or R 2 and/or R 3 are protected, if necessary, by known methods to give, after removal by known methods of protective groups, if any, possibly present in Y and/or R 2 and/or R 3 , a compound of general formula (II).
- Compounds of general formula (I) prepared according to the invention and their pharmaceutically acceptable salts are useful agents for the treatment of cardiovascular disorders such as heart failure and hypertension.
- said compounds (I) show good affinity for the receptor site of the Na + ,K +- ATPase and behave as partial agonists on the enzimatic activity of the Na + ,K +- ATPase.
- Systolic blood pressure (SBP) and heart rate (HR) were measured, by the tail cuff method, in young prehypertensive male rats (MHS or SHR) strains before the development of hypertension (4 weeks of age) for recording the basal values of SBP.
- MHS or SHR young prehypertensive male rats
- Groups of 7 rats were formed and subdivided in control and treated groups.
- the control group received only Methocel.
- SBP and HR were measured weekly 6 and 24 hrs after treatment. Alter 5 weeks of treatment, when hypertension was fully developed in the control group (9 weeks of age), washout was started for at least one week, to verify whether the treatment mantained blood pressure low or reestabtished the basal values.
- the validity of this procedure for detecting an hypotensive activity had been previously tested for blockers, which did not produce any hypotensive effect when acutely given to hypertensive rats (SHR), but were effective in preventing the development of hypertension when administered starting from weaning for more than 5 weeks. (Takeda K. et al., Japan J. Pharmacol., 1979, 29, 171; Takeda K. et al. Japan J. Pharmacol., 1982, 32, 283; Richer C. et al. Eur. J. Pharmacol, 1978, 47, 393).
- the crude product was purified by flash-chromatography (Si0 2 ) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 0.15 g of the title compound (I-ag) as hydroiodide, white solid.
- the crude product was purified by flash-chromatography (Si0 2 ) using chloroform/methanol/28% ammonium hydroxide 89/10/1 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethanol to give 0.20 g of the title compound (I-ah) as a white solid.
- the crude product was purified by flash-chromatography (Si0 2 ) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was crystallized from ethanol/ethyl acetate to give 0.25 g of the title compound (1-an)-as a white solid.
- a solution of 0.29 ml of diethyl azodicarboxylate was added dropwise, under nitrogen, to a solution of 3.75 g of 3 ⁇ -(2-hydroxypropoxy)-17 ⁇ -(2-(1,3-dioxolanyl))-5 ⁇ -androstan-14 ⁇ -ol, 1.24 g of phthalimide and 2.50 g of triphenylphosphine in 35 ml of tetrahydrofuran at room temperature. After 2 hrs the solvent was removed in vacuo, the crude product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
- the crude product was purified by flash-chromatography (Si0 2 ) using as eluant n-hexane/ethyl acetate 70/30 to give 2.11 g of 3-,8-formylmethoxy-17 ⁇ -(2-(1,3-dioxolanyl))-5 ⁇ -androstan-14 ⁇ -ol as a white waxy solid.
- the crude product was purified by flash-chromatography (Si0 2 ) using n-hexane/ethyl acetate 80/20 as eluant to give 1.70 g of 3 ⁇ -(2-hydroxyethoxy)-17 ⁇ -(2-(1,3-dioxolanyl))-5 ⁇ -androstan-14 ⁇ -ol as a white solid.
- a solution of 0.60 ml of diethyl azodicarboxylate was added dropwise, under nitrogen, to a solution of 1.65 g of 3 ⁇ -(2-hydroxyethoxy)-17 ⁇ -(2-(1,3-dioxolanyl))-5 ⁇ -androstan-14 ⁇ -ol, 0.60 g of phthalimide and 1.00 g of triphenylphosphine in 15 ml of tetrahydrofuran was stirred at room temperature. After 2 hrs the solvent was removed in vacuo, the crude product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
- the title compound (II-d) (2.70 g) was obtained as a dense oil starting from 3.20 g of 17 ⁇ -(2-(1,3-dioxolanyl))-5 ⁇ -androstane-3 ⁇ ,14 ⁇ -diol (see Prepn. 1) and 20.0 g of 1-(3-chloropropyl)pyrrolidine using the same procedure described in Prepn. 3.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4227626 | 1992-08-20 | ||
DE4227626A DE4227626C2 (de) | 1992-08-20 | 1992-08-20 | 17-Hydrazonomethyl-14ß-hydroxy-5ß-androstanderivate, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammensetzungen |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0583606A2 true EP0583606A2 (fr) | 1994-02-23 |
EP0583606A3 EP0583606A3 (fr) | 1995-04-05 |
Family
ID=6466001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP93111120A Ceased EP0583606A3 (fr) | 1992-08-20 | 1993-07-12 | Nouveaux hydrazono-5-béta, 14-béta-androstanes cardioactifs, procédé pour leur préparation et les compositions pharmaceutiques les renfermant. |
Country Status (7)
Country | Link |
---|---|
US (1) | US5538960A (fr) |
EP (1) | EP0583606A3 (fr) |
JP (1) | JPH06184187A (fr) |
KR (1) | KR940003963A (fr) |
CA (1) | CA2103824A1 (fr) |
DE (1) | DE4227626C2 (fr) |
ZA (1) | ZA935862B (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0688786A1 (fr) * | 1994-06-13 | 1995-12-27 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Nouveau dérivés hydrazino et hydroxyamino-14-bêta-hydroxyandrostanes actifs sur le système cardiovasculaire, un procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0710646A1 (fr) * | 1994-11-07 | 1996-05-08 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Dérivés du 7a-méthylperhydroindène-3a-ol 1,5-disubstitué, actifs sur le système cardiovasculaire, procédés de leur préparation et compositions pharmaceutiques les contenant |
CN103242406A (zh) * | 2013-05-19 | 2013-08-14 | 广西师范学院 | 去氢表雄酮芳香醛吖嗪甾体化合物及其合成方法和在制备抗肿瘤药物中的应用 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1282289B1 (it) * | 1995-06-23 | 1998-03-16 | Sigma Tau Ind Farmaceuti | 17-idrossiimminoalchil e 17-idrossiimminometilalchenil ciclopentaperidrofenantreni attivi sul sistema cardiovascolare, |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD237170A1 (de) * | 1984-01-04 | 1986-07-02 | Inst Molekularbiologie Ak | Verfahren zur herstellung herzwirksamer 14 beta-hydroxy-androstan-glykoside |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4460509A (en) * | 1981-08-19 | 1984-07-17 | Beth Israel Medical Center | Chemical synthesis |
US5382661A (en) * | 1985-09-12 | 1995-01-17 | The Upjohn Company | Pyrazinylpiperazinyl steroids |
DE4227605C2 (de) * | 1992-08-20 | 1995-02-16 | Sigma Tau Ind Farmaceuti | 17-Hydroxyiminomethyl-14beta-hydroxy-5ß-androstan-Derivate, Verfahren zu deren Herstellung und pharmazeutische Zusammensetzungen, die dieselben enthalten |
-
1992
- 1992-08-20 DE DE4227626A patent/DE4227626C2/de not_active Expired - Fee Related
-
1993
- 1993-07-12 EP EP93111120A patent/EP0583606A3/fr not_active Ceased
- 1993-08-11 CA CA002103824A patent/CA2103824A1/fr not_active Abandoned
- 1993-08-12 ZA ZA935862A patent/ZA935862B/xx unknown
- 1993-08-16 US US08/106,638 patent/US5538960A/en not_active Expired - Fee Related
- 1993-08-18 JP JP5204042A patent/JPH06184187A/ja active Pending
- 1993-08-20 KR KR1019930016225A patent/KR940003963A/ko not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD237170A1 (de) * | 1984-01-04 | 1986-07-02 | Inst Molekularbiologie Ak | Verfahren zur herstellung herzwirksamer 14 beta-hydroxy-androstan-glykoside |
Non-Patent Citations (20)
Title |
---|
AUSTRALIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol.NS2, no.1, 1973 pages 9 - 20 J. BOUTAGY ET AL 'Cardenolide Analogs. III. Synthesis of 17-alpha- and 17-beta-(alpha,beta-unsaturated) esters, ketones, nitriles and related derivatives from digitoxigenin' * |
AUSTRALIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol.NS2, no.2, 1973 pages 41 - 46 J. BOUTAGY ET AL 'Cardenolide Analogues IV. Inhibition of Na+, K+ - ATPase' * |
B. TESTA 'ADVANCES IN DRUG RESEARCH, VOLUME 19' 1990 , ACADEMIC PRESS , LONDON, GB * pages 535-545, particularly pages 536-538, compounds CCVII, CCXVII and CCXXVI, table 9, and page 539, paragraph 2 * * |
Circ. Response. Vol 38(4) pp321-326, (1976) * |
Clin. Sci. 77, p 541-545 (1980) * |
Endocrinology 1992, 131, p 3077 * |
EXPERIENTIA, vol.33, no.6, 15 June 1977, BASEL CH pages 697 - 703 T. G]NTERT ET AL 'Cardiac Glycosides: Prerequisites for the Development of new cardiotonic compounds' * |
Goodman & Gillmann "The Pharmacological Basis of Therapetics, 7th Ed, p 729-730 * |
Hypertens. 1991, 17, p 930-935 * |
Hypertens. 1994, 12, p 569-576 * |
Hypertension 1993, 22 p 178-187 * |
Hypertension 1994, 23(2), p 1087-1090 * |
J.Hypertens. 1994, 12, p 549-560 * |
JOURNAL OF CHEMICAL RESEARCH SYNOPSES, no.7, 1987 pages 218 - 219 M. KABAT ET AL 'Synthesis of 3-beta-rhamno syloxy-5-beta,14-beta-androstan-14-ol and its 17-acetoxy and 17-hydroxy derivatives' * |
JOURNAL OF MEDICINAL CHEMISTRY, vol.21, no.3, March 1978, WASHINGTON US pages 284 - 288 A. GELBART ET AL 'Cardenolide Analogues. 7. Synthesis and Biological Activity of Some New Steroidal Guanylhydrazones' * |
Merck Index, 11th Ed, p 497 and 1091 * |
Proc. Soc.Exp.Biol.Med.1981 * |
Proceedings of the Congress of the Italian Society of Hypertension, Pisa, Oct. 1994 * |
QUATITATIVE STRUCTURE ACTIVITY RELATIONSHIPS, vol.7, 1988, WEINHEIM, DE pages 160 - 165 W. SCH\NFELD ET AL 'A Free-Wilson Analysis of 5-beta,14-beta-Androstane Derivatives Inhibiting the Na/K - ATPase from Human Heart' * |
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol.191, no.2, 1974 pages 219 - 231 R. THOMAS ET AL 'Cardenolide Analogues. V. Cardiotonic Activity of Semisynthetic Analogs of Digitoxigenin' * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0688786A1 (fr) * | 1994-06-13 | 1995-12-27 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Nouveau dérivés hydrazino et hydroxyamino-14-bêta-hydroxyandrostanes actifs sur le système cardiovasculaire, un procédé pour leur préparation et compositions pharmaceutiques les contenant |
EP0710646A1 (fr) * | 1994-11-07 | 1996-05-08 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Dérivés du 7a-méthylperhydroindène-3a-ol 1,5-disubstitué, actifs sur le système cardiovasculaire, procédés de leur préparation et compositions pharmaceutiques les contenant |
CN103242406A (zh) * | 2013-05-19 | 2013-08-14 | 广西师范学院 | 去氢表雄酮芳香醛吖嗪甾体化合物及其合成方法和在制备抗肿瘤药物中的应用 |
CN103242406B (zh) * | 2013-05-19 | 2016-10-05 | 广西师范学院 | 去氢表雄酮芳香醛吖嗪甾体化合物及其合成方法和在制备抗肿瘤药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
KR940003963A (ko) | 1994-03-14 |
JPH06184187A (ja) | 1994-07-05 |
EP0583606A3 (fr) | 1995-04-05 |
CA2103824A1 (fr) | 1994-02-21 |
ZA935862B (en) | 1994-03-09 |
DE4227626A1 (de) | 1994-05-11 |
US5538960A (en) | 1996-07-23 |
DE4227626C2 (de) | 1994-11-17 |
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